ABSTRACT The inflammatory arthritides constitute a group of complex, multifactorial, autoimmune disorders characterized by chronic synovitis that, when left untreated, can lead to joint destruction, deformity and increase morbidity and all-cause mortality. Arguably the most common forms are rheumatoid (RA) and psoriatic arthritis (PsA), which combined affect nearly 2% of the population. The last three decades have witnessed impressive advances in the understanding of disease pathogenesis and the therapeutic outcomes. In fact, the use of methotrexate first, and the subsequent incorporation of anti-TNF (TNFi) and anti-IL-17 (IL-17i) therapies (?biologics?) has led to substantial improvements in rheumatoid and psoriatic clinical outcomes, enhancing the quality of life for millions of patients with inflammatory arthritis (and skin disease). Despite this progress, there are two main questions that remain unanswered: 1) Why do up to half of RA and PsA subjects with moderate to severe arthritis not respond appropriately to these agents? and 2) Why does a significant proportion of patients develop paradoxical autoimmune disease, most notably psoriasis with TNFi and inflammatory bowel disease (IBD) with IL-17i? Pharmacomicrobiomics ? a novel area of research that investigates the effect of variations within the human microbiome on drugs ? promises to overcome these barriers and facilitate precision medicine approaches in cancer and autoimmunity. Methotrexate (MTX), a dihydrofolate (DHF) reductase inhibitor, remains the anchor drug for the treatment of RA and is used widely throughout the world for psoriasis and PsA. While quite effective, oral MTX achieves significant results in 40% of patients and remission rates in only a quarter of them. It is well established that the inter-individual bioavailability of MTX is extremely variable, ranging from 10 to 80%. The reasons for these are likely multifactorial, but the intestinal microbiome and its enzymatic machinery are likely to play a significant role, since animals kept under germ-free conditions are unable to absorb the drug or its metabolites. Our multidisciplinary team composed of rheumatologists, bioinformaticians, and microbiome researchers will address our overarching goal to study: a) how MTX and biologic therapies affect the intestinal microbiome in RA and PsA patients; b) whether changes observed in the microbiome following IL-17i lead to local (intestinal) pro-inflammatory events that could ultimately explain the higher frequency of overt IBD in PsA patients; and c) whether baseline intestinal microbiome could predict the immunomodulatory responses to MTX and biologic (IL-17i and TNFi) therapies. We believe that the results of our highly translational, innovative studies will directly influence therapeutic approaches for the treatment of RA and PsA and offer a more personalized approach in which the clinical efficacy response and/or adverse events development would be predicted in any given patient about to initiate MTX and/or IL-17 and TNF blockers, ultimately avoiding wasteful health expenditures (~$25,000/year/patient in direct costs alone for any biologic therapy).